MXPA02008059A

MXPA02008059A - Biomodulated multiparticulate formulations.

Info

Publication number: MXPA02008059A
Application number: MXPA02008059A
Authority: MX
Inventors: Anne Billotte
Original assignee: Pfizer
Priority date: 2001-09-04
Filing date: 2002-08-19
Publication date: 2003-04-09
Also published as: CA2400565A1; JP2003128544A; EP1287821A1; GB0121436D0; BR0203501A

Abstract

The present invention is concerned with means for adjusting the bioavailability of atorvastatin calcium by modulating its rate of release from multiparticulate formulations and with multiparticulate formulations, especially tablets and capsules, having said modulated rate of release.

Description

FORMULATIONS IN BIOMODULATED MULTIPARTICLES FIELD OF THE INVENTION The present invention relates to means for adjusting the bioavailability of calcium atorvastatin by modulating the rate of release from its multiparticulate formulations, especially tablets and capsules, having said rate of modulated release.

PREVIOUS ART Calcium atorvastatin is a selective competitive inhibitor of HMG-CoA that has a potent lipid lowering activity that is useful as a hypocholesterolemic and / or hypolipidemic agent. It is the subject of European patent No. 0409281 and is currently sold under the name "Lipitor ™".

European Patent No. 0680320 discloses pharmaceutical compositions for the peroral treatment of hyperlipidemia and hypercholesterolemia comprising atorvastatin calcium and at least one pharmaceutically acceptable metal salt additive designed to protect the active drug from any degrading environment or processor, as well as to preserve it from photochemical decomposition during storage. A particularly preferred additive for this purpose is calcium carbonate. Typically, such compositions comprise from 1% to 50% by weight of calcium atorvastatin and from 5% to 50% by weight of calcium carbonate and can be in the form of powders, tablets, dispersible granules, capsules or wafers. There is no reference in the European patent to pharmaceutically acceptable additives such as metal salts that act as biomodulators to alter the release rate of calcium atorvastatin and therefore its bioavailability.

The term "biomodulator" means a substance used in a formulation that has an effect on the release rate of the active agent and can therefore be used to regulate its bioavailability. The biomodulators can have a positive effect, that is, their presence can serve to increase the rate of release and therefore, the bioavailability of the active agent or, as in the present invention, can have a negative effect because their presence suppresses the speed of release and therefore the bioavailability of the active agent. By using an appropriate amount of a suitable biomodulator it is possible to optimize the rate of release and bioavailability of the active agent.

In the formulations of European patent No. 0680320 which do not occur in multiparticles, it has been found that the presence of a pharmaceutically acceptable metal salt type additive has a positive biomodulating effect because increasing its content serves to increase the release rate and the bioavailability of calcium atorvastatin. Unfortunately, the effect of reducing the calcium carbonate content on stability attenuates the use of calcium carbonate as a biomodulator in such formulations. In others words, the bioavailability of calcium atorvastatin is maximized in the interests of stability.

Surprisingly, it has now been found that, in contrast to formulations that do not occur in multiparticles, multi-particle formulations comprising calcium atorvastatin and calcium carbonate have a relatively poor release rate and bioavailability. On the other hand, formulations lacking calcium carbonate not only remain stable, but exhibit a release rate and bioavailability very similar to formulations that do not occur in multiparticles containing calcium carbonate, for example, commercially available tablets. . Therefore, calcium carbonate still behaves as a biomodulator, but unexpectedly in a reverse sense to that observed in formulations that do not occur in multiparticles. This dichotomy in the behavior of calcium carbonate between multiparticle formulations and those that do not occur in multiparticles has not yet been satisfactorily explained.

Using the multiparticulate formulations of the invention it is possible, by adjusting the calcium carbonate loading, to both retain the stability and modulate the rate at which the calcium atorvastatin is released. By judiciously including the correct amount of calcium carbonate, it is possible for the first time to provide a formulation that has a release rate that is lower than that of formulations that do not occur in particles described in the prior art and a bioavailability especially adjusted to the needs of the patient. In other words, by using a multiparticulate formulation according to the invention, the release rate and bioavailability of calcium atorvastatin can be optimized for the particular treatment a patient undergoes.

SUMMARY OF THE INVENTION The present invention provides a means for adjusting the bioavailability of calcium atorvastatin by modulating its release rate from its multiparticulate formulations. Specifically, there are provided: (a) a multiparticulate formulation having a bioavailability comparable to that of a non-multiparticulate formulation containing CaCO3, a formulation comprising calcium atorvastatin and a pharmaceutically acceptable carrier, diluent or excipient other than calcium carbonate, and (b) a multiparticulate formulation having an optimized bioavailability that additionally comprises a biomodulator. A preferred biomodulator for the purposes of the invention is calcium carbonate.

The use of both formulations is also provided as drugs for the treatment of hyperlipidemia and hypercholesterolemia.

The tablets according to the invention may contain vehicles, such as calcium carbonate, dibasic calcium phosphate, glycine, lactose, mannitol, microcrystalline cellulose, sodium citrate and starch (preferably corn starch, potato or tapioca), disintegrating agents, such as sodium croscarmellose, sodium starch glycolate and certain silicates, and granulation binders, such as acacia, bentonite, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone, sorbitol, sucrose and triglycerides . Lubricating agents may also be present, such as glyceryl behenate, magnesium stearate, PEG, stearic acid and talc, wetting agents, such as sodium lauryl sulfate, antioxidant agents, coloring agents, flavoring agents and preservatives.

The tablets of the invention can be manufactured by any standard procedure, for example, by direct compression, granulation (wet, dry, or via melt), coagulation, and extrusion. The cores of the tablets can be monolayer or multilayer and can be coated or left uncoated.

Similar compositions can be employed as fillers in the capsules of the invention. The gelatin, HPMC and starch capsules are particularly suitable for this purpose. Preferred vehicles include cellulose, high Mw polyethylene glycols, lactose and starch.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the disparity of release rates between the multiparticulate formulation of Example 1 containing CaCO3 and a commercial Lipitor ™ tablet containing 30% by weight of CaC3, wherein: D =% of solution T = Time (min) C = tablet containing CaCO3 A = atorvastatin 10%, CaCO3 30%, AcDiSol 5%, pellets of lactose / Avicel Figure 2 illustrates the disparity of bioequivalence between the formulation in multiparticles of Example 1 containing CaC3 and a commercial Lipitor ™ tablet containing 30% by weight of CaC3, where: D =% of solution T = Time (min) C = tablet containing CaCO3 A = atorvastatin 10% , CaCO3 30%, AcDiSol 5%, lactose pellets / Avicel Figure 3 illustrates the similarity of the release rates of the CaCO3-free multi-particle formulation of Example 2 and a commercial Lipitor ™ tablet containing 30% by weight of CaCO3, where: D =% of solution T = Time (min. ) C = tablet containing CaCO3 A = atorvastatin 10%, AcDiSol 15%, pellets of lactose / Avicel Figure 4 illustrates the similarity of the bioequivalence of the multiparticulate CaCO3-free formulation of Example 2 and a commercial Lipitor ™ tablet containing 30% by weight of CaCO3, wherein: D =% dissolution T = Time (min) C = tablet containing CaC03 A = atorvastatin 10%, AcDiSol 15%, pellets of lactose / Avicel DESCRIPTION OF THE PREFERRED MODALITY EXAMPLES Uniformly mixed material suitable for the preparation of multiparticulate formulations according to the invention can be obtained by any of the methods described in the examples. The resulting material is extruded and transformed into spheres to give pellets that can be filled into capsules or compressed into tablets.

EXAMPLE 1 (COMPARATIVE) PREPARATION OF A FORMULATION IN MULTI PARTICLES OF CALCIUM ATORVASTATIN COMPRISING 10% OF CALCIUM ATORVASTATIN, 30% OF CaCO3, AVICEL PH101 / LOACTOSE 110M (1: 1) AND 5% OF AcDiSol Protocol A routine method of mixing / screening was used. The ingredients were weighed directly into a suitable container and mixed for 15 minutes using a Turbula mixer. The resulting mixture was sifted through a 500 μm mesh screen. Mixing and sieving were repeated followed by a final mixing of 15 minutes.

The homogeneity of the mixture was checked by HPLC and a% power of 98-102% was achieved with RSD < 5%.

The mixture was kneaded wet with water or 0.1 M Tris buffer until the mixture broke cleanly when compressed. Then, it was gradually fed into a small scale extruder (Caleva model 15) and the extrudate was collected. The extrudate was transformed into spheres (Caleva model 250) at approximately 600 rpm for 5-10 minutes. The resulting pellets were transferred to a tray and dried in an oven at 50 ° C overnight. Finally, these pellets can be filled into capsules or compressed into tablets.

The tablets had a bulk density of approximately 10% and approximately 97% were in the size range of 500-1200 μm.

Results The release profile of calcium atorvastatin from multiparticulate systems was evaluated by two methods: (a) Release speed Pharmacopoeia method under immersion conditions using a phosphate buffer solution at pH 6.8 to determine the% release of calcium atorvastatin from the multiparticles: Baskets: 100 rpm Medium: potassium dihydrogen-potassium orthophosphate 0.05 M adjusted to pH 6.8 using 10 M potassium hydroxide (900 ml / tank) Temperature: 37 ° C Path length: 1 cm Wavelength: 244 nm Ei1: 399 Sample weight: 400 mg in capsules Result: approximately 100% release within 15 minutes. (b) Bioequivalence Method without immersion using an acetate buffer solution at pH 4.5 to discriminate between bioequivalent and non-bioequivalent formulations of calcium atorvastatin: Pallets: 50 rpm Medium: 0.05 M sodium acetate adjusted to pH 4.5 using HCl (500 ml / tank) Temperature: 37 ° C Length of travel: 1 cm Wavelength: 244 nm E11: 399 Sample weight: 400 mg in capsules Conclusion As shown in Figures 1 and 2, the release profile of the multiparticulate formulation of Example 1 containing CaC 3 was significantly less than that of a tablet containing CaC 3, ie, the multiparticulate formulation of the example 1 containing CaCO3 was not bioequivalent to the tablet containing CaC? 3 corresponding to the prior art. EXAMPLE 2 PREPARATION OF A FORMULATION IN MULTIPARTICLES OF CALCIUM ATORVASTATIN COMPRISING 10% OF CALCIUM ATORVASTATIN, AVICEL PH101 / LOACTOSE 110M (1: 1) AND 15% OF AcDiSol Protocol The multiparticulate formulation of Example 2 was prepared according to the procedure of Example 1; it was found that the CaC-3-free mixture was easier to extrude / spheronize than the mixture of Example 1 containing CaCO3- Results As before, the release profile of calcium atorvastatin from the multiparticles was evaluated using the methods described in example 1.

Conclusion As shown in Figures 3 and 4, the release profile of the multiparticulate formulation free of CaCO3 from Example 2 was very similar to that of a tablet containing CaC3, that is, the multiparticulate formulation was found unexpectedly. CaCO3-free of Example 2 was bioequivalent to a tablet containing CaCO3 corresponding to the prior art.

The multiparticulate formulation of Example 1 containing CaCO3 was difficult to extrude / spheronize, showed poor release rate of calcium atorvastatin (only about 40% after 10 minutes) and was not bioequivalent with a tablet containing CaC3. Omitting the CaC03 component (example 2), it was unexpectedly possible to produce a multiparticulate formulation having a release rate and bioequivalence very similar to those of the commercial tablet containing CaC03. It follows that by including an appropriate amount of CaCO3 in the multiparticulate formulation of Example 2 it would be possible to reduce the release rate of calcium atorvastatin and its bioavailability to adjust the needs of individual patients.

Claims

1. A multi-particle formulation, comprising calcium atorvastatin and a pharmaceutically acceptable carrier, diluent or excipient different from calcium carbonate.

2. A multi-particle formulation in accordance with the claim 1, formulation that additionally comprises a biomodulator.

3. A multi-particle formulation in accordance with the claim 2, wherein said biomodulator is calcium carbonate.

4. A multi-particle formulation according to any one of claims 1 to 3, which formulation is in the form of a tablet or a capsule.

5. A multi-particle formulation according to any one of claims 1 to 4, for use as a medicament.

6. The use of calcium atorvastatin in the manufacture of a medicament, a medication that is in the form of a multiparticulate formulation for oral administration in the treatment of hyperlipidemia.

7. The use of calcium atorvastatin in the manufacture of a medicament, a medication that is in the form of a multiparticulate formulation for oral administration in the treatment of hypercholesterolemia.

8. The use of calcium atorvastatin combined with a biomodulator in the manufacture of a medicament, a medication that is in the form of a multiparticulate formulation for oral administration in the treatment of hyperlipidemia.

9. The use of calcium atorvastatin combined with a biomodulator in the manufacture of a medicament, a medicament that is in the form of a multiparticulate formulation for oral administration in the treatment of hypercholesterolemia.

10. The use of calcium atorvastatin combined with a biomodulator according to claim 8 or 9, wherein said biomodulator is calcium carbonate.

11. The use of calcium atorvastatin combined with a biomodulator according to any of claims 6 to 10, wherein said medicament is in the form of a tablet or a capsule.